Chronic orthostatic intolerance takes the form of postural tachycardia syndrome (POTS) in many patients. POTS pathophysiology is heterogeneous but frequently related to increased sympathetic activation and often accompanied by hyperpnea without tachypnea. Cerebral blood flow is reduced by hypocapnia and systemic vasoregulation is also detrimentally affected. We hypothesize that excessive baroreflex unloading during orthostatic stress is the initiating event in POTS resulting in 1) reduced inhibition of chemoreceptor activity centrally and 2) stimulation of peripheral chemoreceptor activity due to sympathetically induced reductions in blood flow to the carotid body. Increased chemoreceptor activity leads to hyperpnea. We will test this hypothesis by comparing POTS patients with orthostatic hyperpnea (N=20) and without orthostatic hyperpnea (N=20), to healthy control subjects (N=15) asking the following research questions: 1) Is the respiratory chemoreflex function abnormal in POTS with hyperpnea and does it affect ventilation, sympathetic activity and baroreflex function differently compared to control subjects? 2) Does baroreflex unloading produce excessive sympathetic and chemoreflex activity, and pulmonary stretch response in POTS patients with hyperpnea compared to POTS patients without hyperpnea and to control subjects? 3) Does sympathetic stimulation unrelated to the baroreflexes affect chemoreflex sensitivity and sympathetic nerve activity in POTS? : To answer these questions we will enroll 40 subjects and 20 age and gender matched control subjects. Experiments will test whether hyperpnea is caused by sympathoexcitation initiated by baroreflex unloading, potentiated by chemoreflexes, and modulated by pulmonary stretch reflexes. Chemoreflex function curves for ventilation and muscle sympathetic nerve activity (MSNA, obtained by peroneal microneurography) will be measured during controlled changes in inhaled CO2 and oxygen. Interactive effects of chemoreceptors on baroreflexes, and baroreflexes on chemoreflexes will be assessed using MSNA, continuous BP assessment, pneumotachography, and measures of central blood flow using impedance methods, and ultrasound. The modified Oxford method will be used to intermittently assess the cardiovagal and sympathetic baroreflex, and will be supplemented by wavelet based continuous assessment of heart rate, BP, MSNA and peripheral blood flow. Hyperpnea and reduced cerebral blood flow is a severely debilitating and poorly tolerated finding in POTS. Prospective data will define the pathophysiological mechanisms involved in hyperpneic POTS in order to develop specific and effective therapy for the illness. Project Narrative Chronic orthostatic intolerance due to the postural tachycardia syndrome (POTS) affects over a million Americans, mostly young women, who are prevented from gainful employ or school attendance. While a rapid heart rate (tachycardia) is the hallmark of the illness, patients often develop hyperventilation and respiratory difficulty which remain unexplained. In the current proposal we will perform sophisticated tests of the circulation and respiration systems to study the causes, mechanisms and potential treatments of upright hyperventilation in POTS.